Archivum Immunologiae et Therapiae Experimentalis

, Volume 63, Issue 6, pp 427–433 | Cite as

Mesenchymal Stromal Cell Therapy in MDR/XDR Tuberculosis: A Concise Review

  • Lavanya Joshi
  • Lakshmi Kiran Chelluri
  • Sumanlatha GaddamEmail author


Multi-drug-resistant (MDR) tuberculosis is a major public health problem worldwide. Drug resistance arises due to non-compliance of antibiotic therapy. Herein, we explored the therapeutic options available ranging from conservative treatment approaches to alternate adjunct therapies such as mesenchymal stromal cell (MSC) therapy interventions. It is attractive to understand the scientific rationale of using cells as drugs, in particular mesenchymal stem/stromal cells. The review dwells and attempts to analyze the mechanistic approaches of the current treatment modalities to modern therapies. MSCs have demonstrated profound capacity to regenerate and repair. They appear to modulate that the activities of dendritic cells regulate T cells, both in vivo and in vitro. While there seems to be some benefit of such therapies, its use warrants further research. The merits and de-merits of autologous therapy/allogeneic therapy are ill understood. The challenges of requirement of large number of cells for infusion, the route of administration, choice of timing are complex issues that need to be addressed. Furthermore, the host immune responses, environmental factors and epigenetic mechanisms compound the problem. Although, clinical studies are being performed using autologous MSCs in different inflammatory models, it is important that such an intervention should be based on sound scientific rationale. The current review examines the immunomodulatory properties of MSCs, its interactions with other cell types, in assessing the basis for autologous/allogeneic cell-based therapies in the treatment of XDR/MDR tuberculosis.


Mesenchymal stem cell therapy Immunomodulation Clinical trials Adjunct therapy 



We thank Staff of the free chest clinic Mahavir PPMDOTS, Tuberculosis Unit, Bhagwan Mahavir Trust.

Conflict of interest

None of the authors of this paper have any conflict of interests.


  1. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822CrossRefPubMedGoogle Scholar
  2. Augello A, Tasso R, Negrini SM et al (2005) Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 35:1482–1490CrossRefPubMedGoogle Scholar
  3. Bingisser RM, Tilbrook PA, Holt PG et al (1998) Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. J Immunol 160:5729–5734PubMedGoogle Scholar
  4. Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98:1076–1084CrossRefPubMedGoogle Scholar
  5. Chelluri LK, Prasad CE, Preethi V et al (2010a) Tumor necrosis factor (alpha) and Interferon-gamma in allogenic mixed cultures of haematopoetic and non-haematopoeitic cell-cell interactions; TB a case study. Internet J Infect Dis 8(1)Google Scholar
  6. Chelluri LK, Prasad CE, Preethi V et al (2010b) Preliminary report on immunomodulation of mesenchymal stem cells in patients with tuberculosis infection. Cytotherapy 12(Suppl 1):55Google Scholar
  7. Corcione A, Benvenuto F, Ferretti E et al (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107:367–372CrossRefPubMedGoogle Scholar
  8. Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28:875–884CrossRefPubMedGoogle Scholar
  9. Di Nicola M, Carlo-Stella C, Magni M et al (2002) Human bone marrow stromal cells suppress T lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843CrossRefPubMedGoogle Scholar
  10. English K, Ryan JM, Tobin L et al (2009) Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4 + CD25(high) forkhead box P3+ regulatory T cells. Clin Exp Immunol 156:149–160PubMedCentralCrossRefPubMedGoogle Scholar
  11. Erices A, Conget P, Minguell JJ (2000) Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 109:235–242CrossRefPubMedGoogle Scholar
  12. Erokhin VV, Vasil’eva IA, Konopliannikov AG et al (2008) Systemic transplantation of autologous mesenchymal stem cells of the bone marrow in the treatment of patients with multidrug-resistant pulmonary tuberculosis. Probl Tuberk Bolezn Legk 10:3–6PubMedGoogle Scholar
  13. Friedenstein AJ (1976) Precursor cells of mechanocytes. Int Rev Cytol 47:327–359CrossRefPubMedGoogle Scholar
  14. Friedenstein AJ, Petrakova KV, Kurolesova AI et al (1968) Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6:230–247CrossRefPubMedGoogle Scholar
  15. Glennie S, Soeiro I, Dyson PJ et al (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105:2821–2827CrossRefPubMedGoogle Scholar
  16. Groh ME, Maitra B, Szekely E et al (2005) Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp Hematol 33:928–934CrossRefPubMedGoogle Scholar
  17. Gronthos S, Franklin DM, Leddy HA et al (2001) Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol 189:54–63CrossRefPubMedGoogle Scholar
  18. Herzog EL, Chai L, Krause DS (2003) Plasticity of marrow-derived stem cells. Blood 102:3483–3493CrossRefPubMedGoogle Scholar
  19. Hoffman RA, Mahidhara RS, Wolf-Johnston AS et al (2002) Differential modulation of CD4 and CD8 T-cell proliferation by induction of nitric oxide synthesis in antigen presenting cells. Transplantation 74:836–845CrossRefPubMedGoogle Scholar
  20. Huang W, La Russa V, Alzoubi A et al (2006) Interleukin-17A: a T-cell derived growth factor for murine and human mesenchymal stem cells. Stem Cells 24:1512–1518CrossRefPubMedGoogle Scholar
  21. in’t Anker PS, Noort WA, Kruisselbrink AB et al (2003a) Non-expanded primary lung and bone marrow-derived mesenchymal stem cells promote the engraftment of umbilical cord blood-derived CD34(+) cells in the NOD/SCID mice. Exp Hematol 31:881–889CrossRefGoogle Scholar
  22. in’t Anker PS, Scherjon SA, Klejiburg-van der Keur C et al (2003b) Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 102:1548–1549CrossRefGoogle Scholar
  23. Ivanova-Todorova E, Bochev I, Mourdjeva M et al (2009) Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunol Lett 126:37–42CrossRefPubMedGoogle Scholar
  24. Javazon EH, Beggs KJ, Flake AW (2004) Mesenchymal stem cells: paradoxes of passaging. Exp Hematol 32:414–425CrossRefPubMedGoogle Scholar
  25. Jiang XX, Zhang Y, Liu B et al (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105:4120–4126CrossRefPubMedGoogle Scholar
  26. Krampera M, Glennie S, Dyson J et al (2003) Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen specific T cells to their cognate peptide. Blood 101:3722–3729CrossRefPubMedGoogle Scholar
  27. Krampera M, Cosmi L, Angeli R et al (2006) Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24:386–398CrossRefPubMedGoogle Scholar
  28. Le Blanc K, Ringdén O (2006) Mesenchymal stem cells: properties and role in clinical bone marrow transplantation. Curr Opin Immunol 18:586–591CrossRefPubMedGoogle Scholar
  29. Le Blanc K, Ringdén O (2007) Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 262:509–525CrossRefPubMedGoogle Scholar
  30. Le Blanc K, Tammik C, Rosendahl K et al (2003a) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31:890–896CrossRefPubMedGoogle Scholar
  31. Le Blanc K, Tammik L, Sundberg B et al (2003b) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20CrossRefPubMedGoogle Scholar
  32. Lin PL, Flynn JL (2010) Understanding latent tuberculosis: a moving target. J Immunol 185:115–122Google Scholar
  33. Lin H, Xu R, Zhang Z et al (2011) Implications of the immunoregulatory functions of mesenchymal stem cells in the treatment of human liver diseases. Cell Mol Immunol 8:19–22PubMedCentralCrossRefPubMedGoogle Scholar
  34. Maccario R, Podesta M, Moretta A et al (2005) Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 90:516–525PubMedGoogle Scholar
  35. Meisel R, Zibert A, Laryea M et al (2004) Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase mediated tryptophan degradation. Blood 103:4619–4621CrossRefPubMedGoogle Scholar
  36. Migliori G, Loddenkemper R, Blasi F et al (2007) 125 years after Robert Koch’s discovery of the tubercle bacillus: the new XDR-TB threat. Is “science” enough to tackle the epidemic? Eur Respir J 29:423–427CrossRefPubMedGoogle Scholar
  37. Moretta A, Bottino C, Vitale M et al (2001) Activating receptors and co-receptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223CrossRefPubMedGoogle Scholar
  38. Nauta AJ, Kruisselbrink AB, Lurvink E et al (2006) Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 177:2080–2087CrossRefPubMedGoogle Scholar
  39. Prockop DJ, Gregory CA, Spees JL (2003) One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci USA 100(Suppl 1):11917–11923PubMedCentralCrossRefPubMedGoogle Scholar
  40. Raghuvanshi S, Sharma P, Singh S et al (2010) Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci USA 107:21653–21658PubMedCentralCrossRefPubMedGoogle Scholar
  41. Rai RC, Bhattacharya D, Das G (2011) Stem cells in infectious diseases: insight and control of infectious disease in global scenario. ISBN 979-953-307-497-8.
  42. Ramasamy R, Fazekasova H, Lam EW et al (2007) Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 83:71–76CrossRefPubMedGoogle Scholar
  43. Rasmusson I, Ringden O, Sundberg B et al (2003) Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 76:1208–1213CrossRefPubMedGoogle Scholar
  44. Ren G, Zhang L, Zhao X et al (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2:141–150CrossRefPubMedGoogle Scholar
  45. Ren G, Su J, Zhang L et al (2009) Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27:1954–1962CrossRefPubMedGoogle Scholar
  46. Ren G, Zhao X, Zhang L et al (2010) Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol 184:2321–2328PubMedCentralCrossRefPubMedGoogle Scholar
  47. Rush S (2010) Trinity Evolution: mesenchymal stem cell allografting in foot and ankle surgery. Foot Ankle Spec 3:140–143CrossRefPubMedGoogle Scholar
  48. Ryan JM, Barry FP, Murphy JM et al (2005) Mesenchymal stem cells avoid allogeneic rejection. J Inflamm 2:8CrossRefGoogle Scholar
  49. Ryan JM, Barry F, Murphy JM et al (2007) Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 149:353–363PubMedCentralCrossRefPubMedGoogle Scholar
  50. Salam MA (2010) MDR/XDR-TB: where do we stand? Bangladesh J Med Sci 9(4):189Google Scholar
  51. Sato K, Ozaki K, Oh I et al (2007) Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109:228–234CrossRefPubMedGoogle Scholar
  52. Shi Y, Hu G, Su J et al (2010) Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res 20:510–518CrossRefPubMedGoogle Scholar
  53. Skrahina A, Hurevich H, Zalutskaya A et al (2012) Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk. Eur Respir J 39:1425–1431PubMedCentralCrossRefPubMedGoogle Scholar
  54. Skrahina A, Ahmed RK, Ferrara G et al (2014) Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir Med 2:108–122CrossRefPubMedGoogle Scholar
  55. Sotiropoulou PA, Perez SA, Gritzapis AD et al (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24:74–85CrossRefPubMedGoogle Scholar
  56. Stagg J, Pommey S, Eliopoulos N et al (2006) Interferon-gamma-stimulated marrow stromal cells: a new type of non-hematopoietic antigen-presenting cell. Blood 107:2570–2577CrossRefPubMedGoogle Scholar
  57. Sudres M, Norol F, Trenado A et al (2006) Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 176:7761–7767CrossRefPubMedGoogle Scholar
  58. Uhlin M, Andersson J, Zumla A et al (2012) Adjunct immunotherapies for tuberculosis. J Infect Dis 205(Suppl 2):S325–S334CrossRefPubMedGoogle Scholar
  59. Von Lüttichau I, Notohamiprodjo M, Wechselberger A et al (2005) Human adult CD34-progenitor cells functionally express the chemokine receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but not CXCR4. Stem Cells Dev 14:329–336CrossRefGoogle Scholar
  60. WHO (2014) Global Tuberculosis Control Report 2014. World Health Organization, Geneva. Accessed 12 Nov 2014
  61. Wong RS (2011) Mesenchymal stem cells: angels or demons? J Biomed Biotechnol 2011:459510PubMedCentralPubMedGoogle Scholar
  62. Xu G, Zhang L, Ren G et al (2007) Immunosuppressive properties of cloned bone marrow mesenchymal stem cells. Cell Res 17:240–248PubMedGoogle Scholar
  63. Zhang W, Ge W, Li C et al (2004) Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev 13:263–271CrossRefPubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2015

Authors and Affiliations

  • Lavanya Joshi
    • 1
  • Lakshmi Kiran Chelluri
    • 2
  • Sumanlatha Gaddam
    • 1
    • 3
    Email author
  1. 1.Department of ImmunologyBhagwan Mahavir Medical Research CenterHyderabadIndia
  2. 2.Transplant Immunology and Stem Cell LaboratoryGlobal HospitalsHyderabadIndia
  3. 3.Department of GeneticsOsmania UniversityHyderabadIndia

Personalised recommendations